Four-component reactions toward fused heterocyclic rings

Article abstract of DOI:10.1021/ol902279m

A multicomponent reaction between H₂, CO, an unsaturated carboxylic acid derivative, and binucleophiles has been discovered. This process represents a combination of diversity-oriented synthesis and multicomponent reactions including amidation and hydroformylation, followed by nucleophilic addition to an N-acyliminium ion allowing the generation of six new bonds. Using π-nucleophiles, the sequence turns into a multicomponent Pictet-Spengler reaction.

Full text of DOI:10.1021/ol902279m

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5314-5317
Four-Component Reactions toward
Fused Heterocyclic Rings
Etienne Airiau,† Nicolas Girard,† Andre´ Mann,*,† Jessica Salvadori,‡ and
Maurizio Taddei‡
Faculte´ de Pharmacie, UMR 7200, CNRS-UniVersite´ de Strasbourg, Laboratoire
d’InnoVation The´rapeutique, 74 route du Rhin, F-67401 Illkirch, France, and
Dipartimento Farmaco Chimico Tecnologico, UniVersita` degli Studi di Siena, Via A.
Moro 2, 53100 Siena, Italy
andre.mann@pharma.u-strasbg.fr
Received October 2, 2009
ABSTRACT
A multicomponent reaction between H2, CO, an unsaturated carboxylic acid derivative, and binucleophiles has been discovered. This process
represents a combination of diversity-oriented synthesis and multicomponent reactions including amidation and hydroformylation, followed
by nucleophilic addition to an N-acyliminium ion allowing the generation of six new bonds. Using π-nucleophiles, the sequence turns into a
multicomponent Pictet-Spengler reaction.
Many efforts have been devoted toward the rational design
of scaffolds using guidelines for the generation of libraries
in medicinal chemistry such as diversity-oriented synthesis
(DOS)1,2 or multicomponent reactions (MCRs).3,4 Thus
innovations in DOS and MCRs based on selectivity, step
economy, and feasibility are actual trends in molecular
science.5
In this respect, hydroformylation of alkenes may be a
source of inspiration. However, although aldehydes produced
by hydroformylation have been integrated in domino pro-
cesses,6,7 there are limited numbers of examples concerning
true MCRs involving gaseous reagents.6 As the generation
of aldehydes by hydroformylation has been beneficial for
several chemical processes,8,9 we plan to experiment a MCR
toward the preparation of fused lactams, popular starting
materials for many chemical transformations (Figure 1).10-13
† CNRS-Universite´ de Strasbourg.
‡ Universita` degli Studi di Siena.
(1) (a) Isambert, N.; Lavilla, R. Chem.-Eur. J. 2008, 14, 8444–8454.
(b) Breit, B.; Schmidt, Y. Chem. ReV. 2008, 108, 2982–2951. (c) Cordier,
C.; Morton, D.; Murrison, S.; Nelson, A.; O’Leary-Steele, C. Nat. Prod.
Rep. 2008, 25, 719–737. (d) Hubel, K.; Lessmann, T.; Waldmann, H. Chem.
(5) For an interesting overview on the need for innovation in
multicomponent reactions, see: Ganem, B. Acc. Chem. Res. 2009, 42,
463–472.
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(2) Nielsen, T. E.; Schreiber, S. L. Angew. Chem., Int. Ed. 2008, 47,
48–56, and references therein
.
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(3) (a) Ugi, I.; Domling, A.; Horl, W. Multicomponent reactions in
organic chemistry. EndeaVour 1994, 18, 115–122. (b) Armstrong, R. M.;
Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem.
(7) (a) Eilbracht, P.; Ba¨rfacker, L.; Buss, C.; Hollmann, C.; Kitsos-
Rzychon, B. E.; Kranemann, C. L.; Rische, T.; Roggenbuck, R.; Schmidt,
A. Chem. ReV. 1999, 99, 3329–3365. (b) Breit, B. Acc. Chem. Res. 2003,
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36, 264–275.
(4) For some selected reviews, see: (a) Gonzalez-Lopez, M.; Shaw, J. T.
Chem. ReV. 2009, 109, 164–189. (b) Akritopoulou-Zanze, I. Curr. Opin.
Chem. Biol. 2008, 12, 324–331. (c) Shestopalov, A. M.; Shestopalov, A. A.;
Rodinovskaya, L. A. Synthesis 2008, 1–25. (d) Banfi, L.; Guanti, G.; Riva,
P.; Basso, A. Curr. Opin. Drug DiscoVery DeV. 2007, 10, 704–714. (e)
(8) (a) Petricci, E.; Mann, A.; Rota, A.; Schoenfelder, A.; Taddei, M.
Org. Lett. 2006, 8, 3725–3727. (b) Petricci, E.; Mann, A.; Salvadori, J.;
Taddei, M. Tetrahedron Lett. 2007, 48, 8501–8504. (c) Spangenberg, T;
Breit, B.; Mann, A. Org. Lett. 2009, 11, 261–264
(9) Airiau, E.; Spangenberg, T.; Girard, N.; Schoenfelder, A.; Salvadori,
J.; Taddei, M.; Mann, A. Chem.-Eur. J. 2008, 14, 10938–10948
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10.1021/ol902279m CCC: $40.75
Published on Web 10/26/2009
 2009 American Chemical Society

microwave (MW) dielectric heating the results were com-
parable with an appreciable saving of time (1 h instead of
12 h, entry 3). From these preliminary results it can be
concluded that the above designed four-ingredient reaction
takes place successfully. It is worth noting that the catalytic
activity of Rh(I) was maintained supress in the presence of
many fuctional groups or additives. Interestingly the dia-
stereomeric ratio of the adducts 5a/5b depended on the acyl-
activation of butenoic acid (1-3: X ) OSu, OMe, OH) and
on the experimental device (autoclave or MW).
Figure 1. Domino MCR reaction orchestrated by Rh(I).
Therefore MCRs were investigated with the following four
ingredients: an alkene having an acyl group, CO, H2, and
binucleophilic substrates, carrying as nucleophiles a primary
amine, and either an oxygen atom or a sp2 carbon. While
the reactivity of the two gases on the alkene is orchestrated
by Rh(I) to reach linear hydroformylation, the complemen-
tary reactivity of both electrophiles and nucleophiles present
in the mixture should produce oxazolidinones with the
generation of six new bonds in a one-pot single step. Bicyclic
5-6 fused lactams of this type are generally prepared using
the Meyers route by thermal cyclodehydration of γ-acid-
aldehydes with an amino-alcohol,14 but the latter are tedious
to prepare and sensitive to reactions conditions.10 Herein we
propose a new chemical sequence with a substantial step
economy by producing in situ the two main reaction partners:
the aldehydes and the secondary amides.
Table 1. Optimization of Domino MCR with 4
entry
X
conditionsa yield of 5a (%)b yield of 5b (%)b
1
2
3
4
5
6
1: OSu autoclavec
1: OSu autoclave
1: OSu MW
2: OMe autoclave
2: OMe MW
58
81
79
6
8
9
45
45
40
35
35
3: OH
MW
For the design and verification of the experimental setup
of the process, various conditions were tested (Table 1).
Xantphos or biphephos were selected as chelating ligands
for Rh(I) to guarantee linear hydroformylation of the alkenoic
acids. All reactions were conducted with an acid catalysis
to promote the domino reaction.9 To determine a suitable
activation for 3-butenoic acid, O-Me or O-succinimidyl
(OSu) ester was investigated. A preliminary experiment
(entry 1) was performed with (R)-phenylglycinol 4 and OSu
ester 1, in the presence of xantphos as the hydroformylative
ligand. Oxazolidinones 5a/b were obtained from the reaction
mixture,11 the trans dia 5a being the major adduct as the
final cyclization is under thermodynamic control. Further-
more, with biphephos as ligand (entry 2), a better yield was
obtained with a similar diastereoselectivity, and under
a Conditions for reactions carried out under MW dielectric heating: ratio
1-3:4 ) 1.2:1; 7 bar H2/CO (1:1), Rh(CO)2acac 1 mol %, biphephos 2
mol %, 150 W, max internal temperature and pressure 70 °C and 10 bar,
pTSA 10 mol %, [amino-alcohol] ) 0.04 M in THF, 1 h. Conditions for
reaction carried out in a stainless steel autoclave: ratio 1-3:4 ) 1.2:1,
Rh(CO)2acac 1 mol %, biphephos 2 mol %, [amino-alcohol] ) 0.04 M in
THF, PPTS 5 mol %, 5 bar H2/CO (1:1), 70 °C, 12 h. b Isolated yield.
c Xantphos as ligand (2 mol %).
In the autoclave with the O-Me ester 2, oxazolidinone 5b
(cis dia) was observed as the only adduct, whereas under
MW irradation a mixture of 5a and 5b was observed
(compare entries 4 and 5). Finally with the free acid 3 (entry
6), a 1:1 mixture of 5a and 5b was obtained under MW
dielectric heating, whereas no reaction was observed in the
autoclave.
Interestingly, in both cases the dissimilar product distribu-
tion reflects two sequences of events.12,13 With the O-
succinimidyl 1, amidation occurs first, followed by the
hydroformylation and formation of the N-acyliminium
derivative. Under thermodynamic control, the latter under-
goes nucleophilic addition to yield the trans oxazolopiperi-
dinone 5a. With the less activated O-Me ester 2 and the acid
3, the hydroformylation initiates the reaction. Then, the newly
formed aldehyde reacts with the binucleophile to form mainly
a cis disubstituted oxazolidine. Finally, amidation on the ester
or acid functions delivered mainly the cis oxazolopiperidone
5b. In the autoclave solely the cis isomer (5b) was obtained
albeit in moderate yield.12,13 However, under microwave
irradiation, the more harsh and heterogeneous conditions gave
the mixture of diasteromers (entries 5 and 6).
(10) Meyers, A. I; Lefker, B. A.; Sowin, T. J.; Westrum, L. J. J. Org.
Chem. 1989, 54, 4243–4246.
(11) For leading references on chiral non-racemic bicyclic lactams, see:
(a) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503–9569. (b)
Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843–9873. For
other preparative methods, see: (c) Amat, M.; Llor, N.; Bosch, J.
Tetrahedron Lett. 1994, 35, 2223–2226. (d) Royer, J.; Husson, H.-P.
Heterocycles 1993, 36, 1493–1496. (e) Micouin, L.; Quirion, J.-C.; Husson,
H.-P. Synth. Commun. 1996, 26, 1605–1611. (f) Allin, S. M.; Thomas, C. I.;
Allard, J. E.; Doyle, K.; Elsegood, M. R. J. Eur. J. Org. Chem. 2005, 19,
4179–4186. (g) Allin, S. M.; Vaidya, D. G.; James, S. L.; Allard, J. E.;
Smith, T. A. D.; McKee, V.; Martin, W. P. Tetrahedron Lett. 2002, 43,
3661–3663. (h) Le Quement, S. T.; Nielsen, T. E.; Meldal, M. J. Comb.
Chem. 2007, 9, 1060–1072.
(12) Bouet, A.; Oudeyer, S.; Dupas, G.; Marsais, F.; Levacher, V.
Tetrahedron: Asymmetry 2008, 19, 2396–2401.
(13) This behavior is in concordance with the results observed by Amat,
who reported the formation of the cis isomer via a multistep sequence based
on the condensation of 5-oxopentanoate with 4. Amat, M.; Bosch, J.;
Hidalgo, J.; Canto, M.; Pe´rez, M.; Llor, N.; Molins, E.; Miravitlles, C.;
Orozco, M.; Luque, J. J. Org. Chem. 2000, 65, 3074–3084.
(14) Couty, F.; Evano, G. In ComprehensiVe Heterocyclic Chemistry
III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J., Eds.;
Elsevier Ltd.: Oxford, 2008; Vol. 11, 409-499.
These preliminary experiments demonstrate that a proper
choice of the acyl-activation in the MCR delivered either
Org. Lett., Vol. 11, No. 22, 2009
5315

Table 2. Domino MCR on Various Amino-alcohols
Table 3. Domino MCR with N-Cbz-Allylglycine O-Su Ester 16
yield (%)b
(trans/cis)c
entry
substratea
product
1
2
3
(S)-phenylglycinol 17
7
10
18: R1 ) Ph
19: R1 ) iPr
20
76 (86/14)
84 (83/17)
80 (88/12)
a Reactions carried out in MW, conditions as in Table 1. b Isolated yield.
c Diastereoselectivity determined by 1H NMR of the crude reaction mixtures.
It has been shown that R-amino acids are possible ligands
for Rh(I) during the hydroformylation of alkenes;16 neverthe-
less we decided to test amino acids 21-25 as possible
binucleophilic partners in the MCR, in noticing that, as
zwitterions, their reactivity as nucleophiles can be questioned.
In return the preparation of oxazolo-pyridinediones can be
at hand in a one-step procedure (Table 4). A literature survey
revealed that this class of compounds is scarcely reported
albeit their potentials for further transformations.12,17 Thus
using the optimal conditions described before, the reaction
of the OSu ester 1 and D-phenylalanine (21) gave compound
26 as a single diastereomer in a good yield (69%).18 Applied
to several aminoacids such as (R)-phenylglycine (22),
L-valine (23), and L-methionine (24), only the corresponding
trans oxazolopyridine-diones 26-29 were obtained as single
diastereomers, as extrapolated from a single crystal X-ray19
obtained for 27. Both autoclave and microwave dielectric
heating produced similar results. This one-pot procedure is
particularly attractive for the obtention of original scaffold
by reacting allylglycine derivative 16 with L-phenylalanine
(25), 30 is obtained as a single diasteromer in 65% yield.
Clearly bicycle 30 is amenable to an azepinone with three
different points of molecular diversity.12,17a,20 The stereo-
chemistry of the adducts 26-30 arising from the above MCR
with the R-amino acids indicates a thermodynamic control.
a A: reactions carried out in autoclave, conditions as in Table 1. B:
reactions carried out in MW, conditions as in Table 1. b Isolated yields.
c Diastereoselectivity determined by 1H NMR of the crude reaction mixtures.
oxazolopiperidones 5a or 5b, in contrast to the intramolecular
strategy in which 5a was favored.9 Finally the conditions
described in entries 2 and 4 were routinely used for the
hydroformylative reactions in either device, respectively.
These results prompted us to extend the procedure with
olefin 1 to other amino-alcohols (6-10) (Table 2). The
expected oxazolopiperidones 11-15 were obtained in mod-
erate to good yields favoring always the trans (11a-15b)
over the cis (11b-15b) adducts.15 Autoclave and MW gave
roughly similar results.
(16) Paganelli, S.; Marchetti, M.; Bianchin, M.; Bertucci, C. J. Mol.
Catal. A: Chem. 2007, 269, 234–239.
To expand the scope of the reaction and increase the
molecular complexity, N-Cbz-allylglycine O-succinimide
ester 16, a chiral masked bielectrophile, was engaged in the
MCR with chiral amino-alcohols (7, 10 and 17) (Table 3).
As expected 7,5-fused bicyclic or tetracyclic heterocycles
18, 19, or 20 were obtained in good yields and diastereomeric
ratios. The trans isomer was always the major adduct.
(17) (a) Bassas, O.; Llor, N.; Santos, M. M. M.; Griera, R.; Molins, E.;
Amat, M.; Bosch, J. Org. Lett. 2005, 7, 2817–2820. (b) Robl, J. A.;
Cimarusti, M. P.; Simpkins, L. M.; Weller, H. N.; Pan, Y. Y.; Malley, M.;
DiMarco, J. D. J. Am. Chem. Soc. 1994, 116, 2348–2355
.
(18) This high selectivity can be explained with the higher lability of
the bond on C8a due to the presence of the carbonyl. This situation allows
a rapid equilibration toward the trans isomer even in the presence of small
amounts of acid .
(19) See Supporting Information for ORTEP of 27.
(20) 3-Aminoazepanones substituted in position 7 have been previously
described in several patents as structures of pharmaceutic interest. See for
example: Burgey, C. S.; Deng, Z. J.; Nguyen, D. N.; Paone, D. L. V.; Shaw,
A. W.; Williams, T. M. WO 2004092166 A2 20041028. Knaup, G. DE
10020818 A1 20011031
(15) The diastereomers were separable by chromatography, allowing
isolation of the major adduct with the yields reported in Table 2. It was
possible to isolate also the cis isomer of compounds 11-15.
5316
Org. Lett., Vol. 11, No. 22, 2009

Table 4. Domino MCR of 1 with Various Amino Acids
Scheme 1. One-Pot, MCR/Pictet-Spengler Reaction
a Rh(CO)2acac 1 mol %, biphephos 2 mol %, 5 bar H2/CO (1:1),
BF3·Et2O 20 mol % b Rh(CO)2acac 1 mol %, biphephos 2 mol %, 5 bar
H2/CO (1:1), pTSA 10 mol %.
For 33, the reaction was performed in presence of pTSA
and a mixture of the tetracyclic adducts 36a,b was obtained
with a good yield, 36a (trans dia) being the major adduct.9
As expected, the MCR/Pictet-Spengler reaction allowed a
very straightforward access to N-containing polycyclic
compounds starting from carefully designed starting materi-
als.
In conclusion a new MCR has been discovered employing
a latent bielectrophile (unsaturated acid derivative) and
binucleophiles. In an autoclave or under MW irradations, a
sequence of four reactions occurred in situ, namely, amide
bond formation, linear hydroformylation, intermolecular
collapse to an N-acyliminium and a final nucleophilic attack.
In this process six new bonds were created in a single step
delivering fused heterocycles with good control of the
diatereoselectivity. This process represents a combination of
DOS and MCR involving gaseous reagents (CO and H2) that
are scarcely exemplified but have great potentialities.
a Conditions as in Table 1. b Reaction carried out in toluene.
c Diastereoselectivity trans/cis > 95/5 in all cases, determined by 1H NMR
of the crude reaction mixture.
More work is necessary to clarify the chronology of the
events.
Finally as transient N-acyliminium ions are powerful
electrophiles, the possibility to extend the MCRs to a one-
pot Pictet-Spengler reaction was examined (Scheme 1).21
For that purpose, enriched aromatic rings such as 3-MeO-
phenethylamine (31), tryptamine (32), or O-Me-tryptophane
(33) were selected as C-nucleophile partners. Running the
MCR with arylamines 31 and 32 in presence of BF3·Et2O,
compounds 34 and 35 were isolated as the expected
Pictet-Spengler adducts in good yields.
Acknowledgment. This work was supported by the
Ministe`re de´le´gue´ a` l′Enseignement Supe´rieur et a` la
Recherche (E.A.) and by MIUR (Rome) within the PRIN
projects 2008.
Supporting Information Available: Detailed experimen-
tal procedures and spectral and analytical data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) For a recent application, see: Chiou, W.-H.; Lin, G.-H.; Hsu, C.-
C.; Chaterpaul, S. J.; Ojima, I. Org. Lett. 2009, 11, 2659–2662.
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